FormalPara Key Summary Points

Why carry out this study?

Dry eye disease is a multifactorial, complex condition that can worsen or develop following corneal refractive surgery.

Neurostimulation has emerged as a new category of treatment options in dry eye that stimulates natural tear production while sparing the ocular surface.

What was learned from the study?

Varenicline solution nasal spray is the first pharmacologic treatment option available with neurostimulation that enhances natural tear production while sparing the ocular surface.

Varenicline solution nasal spray could hold promise as a treatment option for patients following laser in situ keratomileusis (LASIK) for minimizing the signs and symptoms of dry eye and avoiding the issues associated with topical medication use.

Introduction

Dry eye disease (DED) is a multifactorial and often chronic condition that significantly affects productivity and quality of life [1, 2]. Its complexity is highlighted in its recent definition: “a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, accompanied by ocular symptoms, where tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles” [3]. Significant innovations in DED treatment have emerged in the past decade, including new topical agents and mechanical and thermal therapies for meibomian gland dysfunction [4,5,6]. These advancements have broadened the therapeutic scope, allowing clinicians to offer more personalized and patient-centric care.

Recent studies emphasize the importance of identifying and managing DED preoperatively to optimize surgical outcomes [7]. Notably, ocular surgeries can exacerbate dry eye symptoms, underscoring the need for perioperative ocular surface optimization. This is especially pertinent for patients undergoing corneal refractive surgery, as these procedures are known to induce postoperative dry eye complaints [8]. The underlying etiology for the development of dry eye following corneal refractive surgeries such as LASIK remains unclear but is thought to be multifactorial [9]. The likely contributing factors include corneal denervation with diminished trophic influence, reduced blink rate, damage to conjunctival goblet cells or alteration in tear film dynamics owing to the change in corneal shape with refractive surgery. Given the transient nature of dryness after LASIK in most cases, it is likely that corneal denervation leading to a decrease in basal/reflex tear production in combination with reduced blink rate is the main driver of symptoms. Regardless of etiology, patients electing to undergo corneal refractive surgery should be treated with dry eye treatments to minimize signs and symptoms in the perioperative period and optimize their outcome [10].

Neurostimulation has emerged as a novel treatment for DED through its role in stimulating natural tear production [11,12,13]. The intranasal tear neurostimulator (ITN) was the first device in this category, delivering microcurrents to the ethmoid branch of the trigeminal nerve in the nasal lining to stimulate basal tear production [12]. More recently, a pharmacologic approach with neurostimulation was FDA-approved: varenicline solution nasal spray (Tyrvaya™, Oyster Point Pharma, Inc.). VNS enhances basal tear production by targeting nicotinic acetylcholine receptors on the trigeminal nerve terminating in the nasal cavity, thus activating tear film production via the parasympathetic pathway [13]. Clinical studies showed that VNS provided a statistically significant improvement in basal tear production compared to vehicle at 4 weeks post-initiation of treatment, with sustained efficacy up to 12 weeks in further studies [13,14,15].

In this investigator-initiated study, we evaluated the safety and effectiveness of VNS in treating DED signs and symptoms following LASIK surgery.

Methods

This was a prospective, randomized, controlled, study performed at a single site (Fargo, ND) in the US (NCT05082974). This study was conducted in compliance with the Declaration of Helsinki and was reviewed and approved by the WCG Institutional Board (20215075). All participants provided written informed consent.

Patient Selection

Forty subjects, age ≥ 18, planning to undergo LASIK were enrolled into the study. Table 1 provides the key inclusion and exclusion criteria.

Table 1 Key inclusion and exclusion criteria are shown
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Randomization, Treatment and Data Collection

Subjects were randomized 1:1 into two groups, with a target enrollment of up to 30 participants per arm. The study group received VNS applied twice daily, while the control group was administered a placebo nasal spray (vehicle: phosphate-buffered saline) with the same frequency. Treatment began 28 days prior to the LASIK procedure and continued for 84 days (approximately 3 months) post-surgery. The day of surgery (Day 0) was established as the baseline for evaluating study endpoints.

The follow-up procedure after LASIK surgery includes several key components. On Day 0, the LASIK procedure was performed on both eyes. Postoperative assessments were scheduled for Day 1, Day 7, Day 28, Day 84 and Day 168, with the final assessment marking approximately 6 months post-surgery and 3 months after the study treatment has ended. Additionally, patients were monitored for adverse events at each visit. There were two main outcome measures. The first main outcome measure was the mean change in the NEI-VFQ-25 score from Day 0 to Day 84 (3 months). The second main outcome measure was the mean change in corneal fluorescein staining from Day 0 to Day 84 as measured using the National Eye Institute (NEI) scale in which the cornea is segmented into five areas of the cornea and each region is scored 0–3. A composite score was created from the five pre-specified areas of the cornea. All outcome measures, including the primary and secondary outcome measures evaluated in this study, are shown and listed in Table 2. Of note, the order of diagnostic testing to evaluate subjects included tear osmolarity, followed by tear break-up time followed by Schirmer testing as it appears in Table 2.

Table 2 Primary and secondary outcome measures
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To evaluate patient-reported outcomes, two subjective self-administered questionnaires were used. The first is the NEI-VFQ 25, a 25-item questionnaire adapted from the National Eye Institute Visual Function Questionnaire (NEI-VFQ) designed to assess the impact of visual impairment on the patient’s health-related quality of life, with a focus on symptoms of ocular irritation. This questionnaire uses a scoring range from 0 (worst) to 100 (best) and is administered at various points: 28 days prior to surgery, on the day of surgery and at Days 28, 84 and 168 post-surgery. The second assessment tool is the Eye Dryness Score (EDS), which quantifies patient discomfort on a visual analog scale ranging from 0 (no discomfort) to 100 (maximum discomfort). Developed for clinical trials on dry eye disease, the EDS has been used in previous studies to evaluate the severity of dry eye symptoms and is conducted at all study visits.

Surgical Procedure

All subjects underwent LASIK using a standard technique. All laser ablation treatments were performed using the wavefront-optimized Wavelight EX500 excimer laser (Alcon, USA). The procedure started with the creation of a 110-μm, 8.6-mm femtosecond laser (Wavelight FS200, Alcon, USA) flap. After flap creation, the excimer laser treatment was performed with up to 150 microns of ablated stromal tissue. Following the excimer laser treatment, the flap was carefully reapproximated and ensured to be in good position. A same-day flap check was performed in all patients. All patients were treated with a combination antibiotic-steroid drop for 4 weeks after the procedure.

Study Drug: Varenicline Solution Nasal Spray (VNS)

The VNS nasal spray mechanism facilitates the administration of a preservative-free, intranasal formulation containing 0.03 mg of varenicline.

Statistical Analyses

Statistical analysis was performed using SAS (version 9.4, SAS Inc, Cary, NC, USA). An analysis of covariance (ANCOVA) model was used to compare VNS and placebo in the mean change from baseline at certain time points (Day 28, Day 84, etc.) for different efficacy endpoints (e.g., NEI VFQ-25, corneal fluorescein staining, EDS and TBUT). The ANCOVA model included treatment as the fixed effect and baseline endpoint value as the covariate.

Statistical analysis was performed using SAS (SAS Inc, Cary, NC, USA). An analysis of covariance (ANCOVA) method was used to conduct the statistical analysis and compare the study versus the placebo group at various time points. A p value < 0.05 was considered statistically significant.

Results

Baseline characteristics of the 40 participants in the analysis are listed in Table 3.

Table 3 Baseline characteristics for both the study and control populations
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The mean baseline NEI-VFQ-25 score was 93.3 ± 5.7 in the study group and 93.3 ± 8.5 in the control group. At Day 28, there was an improvement from baseline of 2.5 ± 5.5 in the study group and 3.7 ± 8.7 in the control group, and the between-group comparison was not statistically significant (P = 0.24). At Day 84, compared to baseline, there was an improvement of 3.4 ± 5.3 in the study group and 5.0 ± 8.7 in the control group. At Day 84, the between-group comparison was not significantly different (P = 0.06). The first primary endpoint of mean change in the NEI-VFQ-25 score at Day 84 compared to baseline was not met. The NEI-VFQ-25 was also administered at 6 months following surgery. At that time point, the mean improvement in the study and control group was 3.7 ± 5.2 and 4.8 ± 8.7, respectively. The between-group comparison was not significantly different (P = 0.13). The NEI-VFQ-25 scores are summarized and shown in Fig. 1.

Fig. 1
figure 1

Graph demonstrating the NEI-VFQ-25 scores at each time point. The between-group comparison P values are shown to compare the study and control (placebo) group at each time point. NEI VFQ National Eye Institute Visual Function Questionnaire, VNS varenicline solution nasal spray

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At Days 1, 7, 28 and 84, the mean change of corneal fluorescein staining scores were – 0.6, 0.0, – 0.4 and – 0.4 in the study group and 0.7, 0.2, 0.1 and 0.1 in the control group, respectively. Although statistical significance was not observed at Days 1 (P = 0.2), 28 (P = 0.7) and 84 (P = 0.6) for the study group compared to the control group, there was directional improvement in the study group at each time point. The fluorescein staining scores are shown in Fig. 2.

Fig. 2
figure 2

Graph showing the NEI corneal fluorescein staining scores at each time point. The between-group comparison P values are shown to compare the study and control (placebo) group at each time point. NEI National Eye Institute, VNS varenicline solution nasal spray

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The mean EDS at baseline was 12.6 ± 11.1 mm in the study group and 13.1 ± 14.7 mm in the control group. At Day 84, compared to baseline, there was a decrease of 1.4 ± 19.1 mm in the study group and 1.0 ± 14.7 mm in the control group. The between-group comparison was not statistically significant (P = 0.9).

Tear osmolarity was obtained and compared to baseline at Days 28 and 84. At baseline, the mean tear osmolarity value was 309.8 ± 11.5 mOsm/l in the study group and 308.6 ± 15.4 mOsm/l in the control group. At Day 28, there was a mean change of – 9.1 ± 14.0 mOsm/l in the study group and – 8.2 ± 15.7 mOsm/l in the control group. At Day 84, there was a mean change of – 11.6 ± 11.4 mOsm/l in the study group and – 9.2 ± 16.2 mOsm/l in the control group. There was a larger numerical reduction in the study group at each time point but the difference between groups was not statistically significant at Days 28 (P = 0.9) and 84 (P = 0.6).

Schirmer test scores were also compared between groups at key time points including Days 28 and 84. At baseline, the mean Schirmer’s score in the study and control group was 20.9 ± 9.5 mm and 19.9 ± 9.9 mm, respectively. At Day 28, there was a mean change of 2.3 ± 5.2 mm in the study group and 0.7 ± 7.9 mm in the control group. At Day 84, the mean change in the study group was 3.9 ± 8.0 mm, and in the control group the mean change was 2.9 ± 8.9 mm. The difference between the two groups was not statistically significant at Days 28 (P = 0.4) or 84 (P = 0.6), but there was a greater numerical improvement in the study group.

The rate of rescue therapy (punctal plug instillation) was identical between groups. No subject in either group underwent punctal plug instillation or had an escalation of dry eye therapy in the postoperative period. For treatment outcomes following LASIK, the visual and refractive outcomes overall were excellent at Days 28 and 84. All 40 subjects from both groups had 20/20 or better uncorrected visual acuity (UCVA) at the Day 84 (3-month) time point. Overall, there were two subjects with residual refractive error at the 3-month time point, one in each group, and overall, 19/20 (95%) subjects in each group had no residual refractive error.

Safety

No adverse events were recorded at any time point in either group.

Discussion

This is the first study to evaluate VNS in treatment of dry eye signs and symptoms following LASIK. As a procedure, LASIK is commonly associated with postoperative dry eye disease, and the findings from this study suggest that VNS could be a potential treatment option to mitigate the signs and symptoms of postoperative dry eye. Although VNS did not demonstrate a statistically significant difference versus placebo in this small trial, a directional improvement was noted. Furthermore, the use VNS offers the potential benefit of sparing the ocular surface in the postoperative period through a unique action that stimulates natural tear production. As a nasal spray, VNS also avoids the exposure of the ocular surface to preservatives and minimizes the potential of trauma to the cornea epithelium and/or LASIK flap.

This trial is not without its limitations. Previous studies leading to VNS’s approval highlighted its efficacy in providing a rapid, significant improvement in dry eye signs and symptoms over 4 weeks, with sustained effects observed over 12 weeks [13, 15]. These studies primarily included subjects with a confirmed diagnosis of dry eye disease and allowed the use of concomitant artificial tears. This study aimed to enroll a subject cohort that mirrored a real-world patient population, and this likely impacted our outcomes. This investigator-initiated study enrolled a distinct young and healthy population, and inclusion criteria did not require a diagnosis of dry eye disease and excluded those with a history of punctal plug instillation. This likely contributed to the absence of rescue therapy needed for either group and also contributed to the absence of meaningful difference between groups with a relatively small sample size.

Monitoring and treating the health of the ocular surface after LASIK is critical for good patient outcomes and satisfaction. Prior studies have shown up to 90% of patients experience dry eye symptoms post-LASIK, regardless of prior history of dry eye disease before undergoing surgery [8]. Despite the aforementioned limitations of this single study, the exploration of VNS as a treatment option in this patient population remains important. Current perioperative care for patients undergoing LASIK often involves the liberal use of artificial tears, despite the challenges and recent concerns associated with their use, including the risk of infectious complications. VNS offers a novel approach by stimulating natural tear production, thus avoiding the drawbacks of topical treatments. While this study observed directional improvements in tear osmolarity, Schirmer test scores, and corneal fluorescein staining in the VNS treatment group, these findings were not statistically significant. However, the trends observed indicate potential benefits of VNS in managing dry eye symptoms post-LASIK, particularly for patients seeking alternatives to topical medications.

Conclusion

Overall, this study contributes valuable insights for clinicians managing dry eye symptoms in refractive surgery patients and highlights the need for alternative treatments beyond traditional topical medications. With a unique means of administration, VNS provides an alternative ocular surface-sparing treatment for the management of ocular lubrication in the perioperative period for refractive surgery patients. Future studies with larger sample sizes and potentially modified inclusion criteria are recommended to evaluate VNS’s effectiveness more comprehensively in the post-refractive surgery setting.